PROJECT SUMMARY Substance Use (SU) and substance use disorders (SUDs) are widely prevalent and pose devastating health, financial and societal costs. The primary goal of the CARRS Center is to understand how sleep and circadian rhythm traits and environmental disruptions during adolescence lead to increased vulnerability for substance abuse. We further aim to test whether manipulation of sleep and circadian factors during adolescence will alter factors associated with increased risk for SU. The incidence of SU and SUDs increases across adolescence, making this sensitive developmental period one of both heightened risk?and heightened opportunity for prevention and intervention. However, to develop effective interventions, we need to identify novel and modifiable risk factors and mechanisms for SUD. Project 2 (P2) of CARRS will test the hypothesis that individual differences in sleep and circadian characteristics during adolescence are associated with self-report, behavioral, and neural indicators of reward function and cognitive control, which in turn are associated with increased risk for SU. Further, P2 tests an experimental intervention that manipulates sleep and circadian rhythms to directly examine its impact on reward function. P2 will study 150 adolescents (age 13?15) with early (n=50) and late (n=100) sleep timing. All participants will complete 2 weeks of home sleep monitoring, followed by an overnight laboratory visit to assess self-report, behavioral, and neuroimaging (fMRI) tasks of cognitive control and reward function, as well as circadian phase via salivary melatonin and molecular rhythms via hair follicles. The Late group will continue to the experimental study, each participant randomized to 2-week manipulation or attentional control conditions (n=50 each). Finally, we include repeated 6-month follow-up assessments of sleep and SU for all participants in P1 and P2 to examine longitudinal associations. Aim 1 is to compare Early versus Late sleepers on sleep/circadian factors and neurobehavioral markers. Dependent variables include circadian phase, sleep duration, and circadian misalignment, as well as self-report, behavioral, and neural measures of cognitive control and reward function. Aim 2 is to probe the acute effects of experimental sleep advance and extension on sleep and circadian rhythms, as well as effects on neurobehavioral markers of SUD risk, in adolescents with late sleep timing (n=100). Our Collaborative Aim (P1/P2) is to examine whether sleep/circadian factors, cognitive control, and reward function predict subsequent SU across follow-up using self-report, behavioral, and neural measures, as well multivariable machine learning approaches (Core C). P2 will draw directly on resources of Core A: Administration, Core B: Phenotyping and Biobanking, and Core C: Data Management and Statistics. Findings from P2 will complement findings on circadian rhythmicity and homeostatic sleep drive from P1 and will provide definitive findings on how manipulation of sleep/circadian rhythms alters cognitive control, reward function, and SU risk in humans, which may, in turn, inform novel sleep and circadian-based interventions to reduce this risk.